2-quinolyl-4(5)-trifluoromethylimidazoles

ABSTRACT

4(5)-Trifluoromethylimidazoles having optional substituents in the 1 and 2 positions are provided. The novel 4(5)trifluoromethylimidazoles are prepared by reacting a 1,1-dihalo3,3,3-trifluoroacetone compound with an appropriate carboxaldehyde and ammonia. The 4(5)-trifluoromethylimidazoles are useful as anti-gout and anti-hyperuricemic agents.

ijnit States atent 1191 Baldwin et al.

1451 June 18, 1974' 2-QUINOLYL-4(5)- TRIFLUOROMETHYLIMIDAZOLES [75] Inventors: John J. Baldwin, Lansdale;

Frederick C. Novello, Berwyn, both of ,Pa.

[73] Assignee: Merck & Co. Inc., Rahway, NJ. 221 Filedi June 21, 1972 21 App]. No.: 265,016

Related US. Application Data [63] Continuation-impart of Ser. No. 885,362, Dec. 15,

1969, abandoned.

[52] US. Cl 260/288 R, 260/250 A, 260/268 H, 260/306.8 R, 260/309 R, 260/296 R,

260/250 R, 424/250, 424/263, 424/258, 424/273 [51] Int. Cl. C07d 33/50, C07d 57/04 [58] Field of Search 260/288 R [56] References Cited OTHER PUBLICATIONS Sarett et al., Chem. Abstr. 74; 1417922. Jordaan et al., Chem. Abstr. 63: 7065b.

Primary Examiner-Donald G. Daus Assistant Examiner-Ralph D. McCloud Attorney, Agent, or Firm-Rudolph J. Anderson, Jr.; J. Jerome Behan; Erma R. Coutts 4 Claims, N0 Drawings 2-QUINOLYL-4( TRIFLUOROMIETIIYLINHDAZOLES BACKGROUND OF THE INVENTION This is a continuation-in-part of applicants copending application No. 885,362 filed Dec. 15, 1969, now abandoned.

FIELD OF THE INVENTION This invention relates to a class of chemical compounds which may be described as 4(5)- trifluoromethylimidazoles. These novel tr'ifluoromethylimidazoles may be substituted in the 2 position by an alkyl group, an aryl group, or a heteroaryl group and in the 1 position by an alkyl group or an hydroxyalkyl group.

DESCRIPTION OF THE PRIOR ART The herein-described 4( 5 )-trifluoromethylimidazoles have utility as anti-gout and anti-hyperuricemic agents.

Gout is a condition affecting humans and lower animals, particularly birds and reptiles, which is characterized by perversion of the purine metabolism resulting in an excess of uric acid in the blood, by attacks of acute arthritis, and by formation of chalky deposits in the cartilages of the joints. These deposits are made up chiefly of urates, or uric acid. Hyperuricemia is a condition characterized by an excess of uric acid in the blood.

Uric acid serves no biochemical function in the body and is merely an end product of purine metabolism. It is well known in the art that the purine bases adenine and guanine, which play key roles in a wide variety of chemical processes, both give rise to uric acid in the body. Adenylic acid and guanylic acid are converted to the free purine bases by destructive metabolic enzymes. A portion of the free purine bases is converted to purine ribonucleotides and the remainder is degraded to the free bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase, converts both xanthine and hypoxanthine to uric acid for excretion.

Although human purine biosynthesis can be inhibited at the stage of formyl glycinimide ribotide by the glutamine antagonists azaserine and 6-diazo-5-oxo-lnorleucine, a high incidence of undesirable side effects precludes their being used clinically for this purpose. In recent years, substantial progress has been made in attempting to control the excessive levels of uric acid in patients afflicted with gout through the use of pharmaceutical agents. Uric acid synthesis has been effectively blocked by the use of allopurinol, 4-hydroxypyrazolo- [3,4-d1-pyrimidine, a compound which is a structural isomer of hypoxanthine. Allopurinol acts as a specific inhibitor of the enzyme xanthine oxidase, which is responsible for the conversion of both hypoxanthine and xanthine to uric acid. As a direct result of the administration of this compound to patients afflicted with gout, part of the uric acid which would normally end up in the urine is replaced instead by the oxypurines, hypoxanthine and xanthine, thus greatly reducing the content of uric acid in serum and urine. Azathioprine has also been employed in patients afflicted by gout to inhibit the excessive purine synthesis, which tends to produce abnormal amounts of uric acid. Other compounds, such as acetylsalicylic acid, thiophenylpyrazolidine, and phenylbutazone have been employed in the treatment of' gout. Many of the existing compounds used in the treatment of gout, however, relieve the inflammation and other symptoms connected SUMMARY OF THE INVENTION An object of this invention is to provide novel 4(5)- trifluoromethylimidazoles which are useful in the treatment of gout and hyperuricemia. A second object of this invention is to describe products which have utility as hypotensive agents and products which are useful in the treatment of bronchoconstriction.

Still another object of this invention is to describe a method for preparing the herein disclosed products as, for example, by reacting a l,l-dihalo-3,3,3- trifluoroacetone with an appropriate carboxaldehyde and ammonia.

Also, included within this invention are the non-toxic pharmaceutically acceptable quaternary salts and alkali metal and alkaline earth metal salts of the 4(5)- trifluoromethylimidazoles, and-those acid salts wherein the substituent in the 2 position is a heterocyclic ring containing at least one nitrogen atom.

DESCRIPTION OF THE PREFERRE EMBODIMENTS The novel imidazoles which are thesubject of the present invention can be structurally depicted as follows:'

di-Iower alkylamino-lower alkyl such as 2- dimethylaminoethyl or l-dimethylamino-2-methyl- 2propyl and the like,

an heterocycle selected from:

pyridyl,

pyridyl N-oxide,

mono-alkyl and dialkyl substituted pyridyl, such as 2,6-dimethyl-4-pyridyl, 4,6-dimethyl-2-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl or 6-methyl-3-pyridyl and the like,

quinolyl,

thiazolyl,

furyl,

thienyl,

cinnolyl,

pyrazinyl,

methoxy substituted pyrazinyl,

l-lower alkylpyrazolyl such as l-methylpyrazolyl and the like,

l-mono-nuclear aryl substituted pyrazolyl wherein the aryl nucleus may be substituted by halo such as chloro, bromo, fluoro or iodo as, for example, I-( 4- cholorophenyl)-4-pyrazolyl and the like, or

l-mono-nuclear aralkyl substituted pyrazolyl such as l-benzyl-4-pyrazolyl and the like, or

mono-nuclear and binuclear aryl such as phenyl, napthyl or substituted phenyl wherein the substituent is halo such as fluoro, bromo, chloro or iodo,

cyano,

carboxy,

carboalkoxy wherein the alkoxy group contains from lcarbons such as methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl,

lower alkyl wherein the alkyl group is a straight or branched chain group containing l-S carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl and pentyl,

lower alkylidene wherein the alkylidene group contains from 2-5 carbons such as ethylidene, propylidene, butylidene and pentylidene,

sulfamoyl,

lower alkylsulfamoyl and di-lower alkylsulfamoyl wherein the alkyl group contains from l-5 carbons, such as methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, butylsulfamoyl, and the like,

lower alkoxy wherein the alkoxy group contains from l-S carbons such as methoxy, ethoxy, butoxy and the like,

lower alkanoylamino wherein the alkyl group contains from 25 carbons such as acetylamino, propionylamino, butyrylamino and the like.

nitro,

amino,

mono-lower alkylamino wherein the alkyl group contains from l-5 carbons, such as methylamino, ethylamino and propylamino,

di-lower alkylamino wherein the alkyl group contains from l5 carbons such as dimethylamino, diethylamino, dibutylamino, and the like,

methylenedioxy,

a fused lower alkylene chain containing from 3-6 carbons such as a propylene, bu'tylene, or pentylene bridge,

the residue formed by reaction of a cyclic anhydride, for example, maleic anhydride, with a primary or secondary aromatic amine wherein the amino moiety is on the Z-phenyl substituent as, for example, the maleamido moiety -NHCO-CH=CH-COOH.

trifluoromethyl substituted imidazolyl such as 4- trifluoromethyl-2-imidazolyl and the like,

lower alkoxymethyleneoxy such as methoxymethyleneoxy and the like, or

di-lower alkylamino-lower alkoxy such as dimethylaminoethoxy or diethylaminoethoxy and the like.

Where the substituenton the imidazole ring is a substituted phenyl group, the phenyl ring may contain from 1-3 substituents. Where the substituent on the phenyl ringis a lower alkylene bridge, the bridge is joined to the phenyl ring on adjacent carbons as, for example, by a 3,4-propylene bridge. Where R is a naphthyl group, the said naphthyl is joined to the imidazole ring at the l or 2 position of the naphthyl ring, Where the substituent on the phenyl ring is methylenedioxy. the oxygen atoms are joined to the phenyl nucleus on adjacent carbons as, for example, at the 3 and 4 positions of the benzene ring.

Also within the scope of the present invention are the pharmaceutically acceptable quaternary salts such as the methiodides and ethiodides where the heterocyclic group in the 2 position contains a nitrogen atom, alkali metal and alkaline earth metal salts, such as the sodium, potassium and calcium salts, and those mineral acid salts such as the hydrochloride salts, wherein the substituent in the 2 position is a heterocyclic ring containing at least one nitrogen atom, such as a pyridine ring.

it should be understood that the l-unsubstituted trifluoromethylimidazoles discussed herein are compounds in which the trifluoromethyl substituent is at either the 4 or 5 position on the imidazole ring. The hydrogen atom on a nitrogen in the imidazole ring is in a state of tautomeric equilibrium, with the result that the 4 and 5 positions are equivalent.

Typical of the compounds within the definition of Formula I and which are useful in the treatment of gout are, for example:

2-( 4-pyridyl )-4( 5 }-trifluoromethylimidazole l-methyl-2-( 4-pyridyl )4-trifluoromethylimidazole 2-(4-thiazolyl)-4(5)-trifluoromethylimidazole 2-( 2-furyl )-4( 5 )-trifluoromethylimidazole l -ethyl-2-(4-thiazolyl-4-trifluoromethylimidazole 2-isopropyl-4( 5 J-trifluoromethylimidazole 2-phenyl-4( 5 )-trifluoromethylimidazole 2-(o-cyanophenyl )-4( 5 )-trifluoromethylimidazole 2-(p-ethylphenyl )-4( 5 )-trifluoromethylimidazole l-propyl-2-phenyl-4-trifluoromethylimidazole 2-vinylphenyl-4( 5 )-trifluoromethylimidazole Z-(p-suIfamoylphenyl )-4( 5 trifluoromethylimidazole 2-( p-rnethylsulfamoyl )-4( 5 trifluoromethylimidazole l-methyl-2-( p-sulfamoylphenyl )-4- trifluoromethylirnidazole l -methyl-2-phenyl5-trifluoromethyiimidazole 2-( p-methoxyphenyl )-4( 5 )-trifluoromethylimidazole 2-( 6-quinolyl )-4( 5 )-trifluoromethylimidazole 2-( 3-furyl )-4( 5 )-trifluoromethylimidazole 2-( 2-thienyl )-4( 5 )-trifluoromethylimidazole 2-( 3,4-methylenedioxyphenyl )4( 5 trifluoromethylimidazole 2-( o-rnethoxyphenyl )-4( 5 )-trifluoromethylimidazole 2-( p-acetylaminophenyl )-4-( 5 trifluoromethylimidazole 2-( p-cyanophenyl )-4( 5 )trifluoromethylimidazole l-methyl-2-( p'methoxyphenyl )-4- trifluoromethylimidazole lmethyl-2-( p-methoxyphenyl )-5- trifluoromethylimidazole Z-(p-dimethylaminophenyl )-4( S trifluoromethylimidazole 2-( S-indanyl )-4( 5 )-trifluoromethylimidazole 2-( 1 -naphthyl )-4( 5 )-trifluoromethylimidazole 2-(3,4-dichlorophenyl)-4(5)- trifluoromethylimidazole 2-(m-ehlorophenyl)-4( 5 )-trifluoromethylimidazole 2-( p-fluorophenyl )-4( 5 )-trifluoromethylimidazole l-methyl-2-( p-chlorophenyl )-4- trifluoromethylimidazole Z-(p-carboxyphenyl )-4( 5 )-trifluoromethylimidazole 2-( 3-cinnolyl )-4( 5 )-trifluoromethylimidazole 2-( Z-naphthyl )-4( 5 )-trifluoromethylimidazole l-methyl-2-(p-acetylaminophenyl )-4- trifluoromethylimidazole and, l-(2-hydroxyethyl )-2-( l-naphthyl)-5- trifluoromethylimidazole Those compounds wherein R,- in Formula I is hydrogen, lower alkyl or hydroxy lower alkyl, and R is naphthyl, pyridyl, quinolyl, thiazolyl, furyl, thienyl, cinnolyl, pyrazinyl and substituted phenyl wherein the substituent is halo, cyano, carboxy, carboalkoxy, lower alkyl, sulfamoyl, lower alkoxy, lower alkanoylamino, nitro, amino, lower mono-alkylamino, lower di-alkylamino, methyleneoxy, a fused alkylene chain or the residue formed by reaction of a cyclic anhydride with an amine. represent a preferred subclass of compounds within thescope of the present invention.

An especially preferred class of compounds are those of the following formula:

wherein R is pyridyl such as 3-pyridyl or 4-pyridyl. As

a whole, these products exhibit particularly good antigout and anti-hyperuricemic activity and constitute a preferred embodiment of this invention.

The products of this invention are effective anti-gout and antihyperuricemic agents in'that they inhibit the action of the enzyme xanthine oxidase and thus reduce the content of uric acid in serum and urine.

In addition, the instant products (I) inhibit a random anti-hypertensive and bronchodilator effect.

Hypertension or high blood pressure is one of the most common of diseases affecting the heart and blood vessels. Aside from morbidity and mortality directly related to the presence of hypertension, the condition plays a prominent role in other cardiovascular diseases particularly coronary atherosclerosis and cerebrovascular disease. Patients with hypertension usually experience more congestive heart failure, hypertensive heart disease, hypertensive encephalopathy and renal failure than people who have normal blood pressure.

And although various drugs are available for the treatment of hypertension, all have their limitations and deficiencies.

The ganglionic blocking agents cause postural hypotension, give poor control of supine blood pressure and cause dry mouth and paralysis of ocular accommodation along with other undesirable effects.

The sympathetic blocking agents are also limited in terms of response in patients due to the production of postural hypotension, fatigue, muscle aching, giddiness and diarrhea.

Furthermore,all patients will not respond to drugs that deplete or interfere with catecholamine metabo- 6 lism. In addition, such drugs possess side effects that limit their usefulness. Thus, for example, hydralazine is limited due to its effect in causing tachycardia and immunologic reactions.

Also, the thiazide diuretics are useful in mild hypertension but in more severe cases must be in combination with other agents since along they are not effective. The thiazides also promote uric acid retention, hyperglycemia and potassium loss.

Due to the limitations and deficiencies of these agents, there is a medical need for a drug to replace them in the management of hypertension.

Those products which exhibit anti-hypertensive activity can be described as follows:

wherein R is hydrogen or lower alkyl such as methyl,

ethyl, propyl or n-butyl and the like, and R is phenyl,

halophenyl such as chlorophenyl or bromophenyl and the like, lower alkylphenyl such as tolyl or ethylphenyl and the like, pyridyl,'lower alkylpyridyl such as 2-methyl-4-pyridylor 6-methyl-3-pyridyl and the like, pyridyl- N-oxide, thiazolyl, lower alkyl such as ethyl or isopropyl and the like, quinolyl, thienyl, di-arylmethyl such as diphenylethyl, lower alkanesulfonamidophenyl, such as methane-or ethanesulfonamidophenyl and the like, or (di-lower alkylaminoalkoxy)phenyl and the like, and the non-toxic pharmacologically acceptable acid addition salts and alkali metal salts thereof.

Illustrative of the products exhibiting this antihypertensive activity are, for example:

2-( 3-pyridyl )-4( 5 )-trifluoromethylimidazole 2-( Z-pyridyl )-4( 5 )-trifluoromethylimidazole 2-( 4-pyridyl )-4( 5 )-trifluoromethylimidazole 2-(4-thiazolyl)-4(5)-trifluoromethylimidazole 2-isopropyl-4( 5 )-trifl uoromethylimidazole 2( 2-thienyl)-4( 5 )-trifluoromethylimidazole 2-( o-chlorophenyl )-4( 5 )-trifluoromethylimidazole 2-( p-chlorophenyl )-4( 5 )-trifluoromethylimidazole 2'-phe'nyl-4( 5 )-trifluoromethylimidazole 2-(p-methylsulfonamidophenyl)-4- trifluoromethylimidazole 2-(p-diethylaminoethoxyphenyl)-4- trifluoromethylimidazole 2-(3rpyridyl-1-oxide)-4-trifluoromethylimidazole Z-diphenylmethyl-4-trifluoromethylimidazole 2-( l-methyl-4-pyrazolyl )-4-trifluoromethylimidazole potensive activity:

N mo t |L 'N/ Rs wherein R is phenyl, halophenyl as, for example, p-

' chlorophenyl and the like, pyridyl as, for example, 3-

pyridyl or 4-pyridyl and the like, lower alkanesulfonamidophenyl as, for example, methanesulfonamidophenyl and the like or lower alkylpyridyl as, for example, 2-methyl-4-pyridyl or 6-methyl-3-pyridyl and the like. The above products and the non-toxic pharmacologically acceptable acid addition salts and alkali metal salts thereof are especially effective hypotensive agents and, therefore, constitute a preferred subclass of compounds within the scope of this inven tion.

The following products are also useful as bronchodilating agents. They are of significant value in the management of the asthmatic patient because they are useful as both prophylactic drugs and as adjuncts in the treatment of prolongedattacks and status asthmaticus. Any attack characterized by a decrease in vital capacity and an increase in residual air would be alleviated by the use of these agents:

wherein R is hydrogen or lower alk'yl, such as methyl, ethyl, propyl and the like and R is pyridyl, lower alkylpyridyl, such as methylpyridyl, ethylpyridyl and the like, thiazolyl, lower alkoxy substituted piperazinyl, such as methoxypiperazinyl and the like or piperidinyl substituted lower alkyl, such as piperidinyl substituted,

butyl and the like, and the non-toxic pharmacologically acceptable acid addition salts and alkali metal salts thcreof.

The following subgroups of compounds exhibits particularly good bronchodilator activity:

it I N/ R5 wherein R and R, are methyl and pyridyl, respectively at the same time or, in the alternative, R is hydrogen when R ispyridyl, methylpyridyl, thiazolyl, or methoxy substituted piperazinyl. This subgroup of compounds is particularly useful in the treatment of bronchoconstriction and, therefore, constitutes a preferred embodiment of this invention.

The compounds of the present invention having the structural formula:

. I N l t wherein R is hydrogen,

lower alkyl,

di-lower alkylamino-lower alkyl,

any of the heterocycles within the definition of R supra,

can be prepared by first reacting a l,l-dihalo-3,3,3- trifluoroacetone compound. such as l,l-dibro mo- 3,3,3-trifluoroacetone, with mild base, such as sodium acetate, aqueous ammonia or potassium carbonate, and then reacting the basic mixture with the appropriate carboxaldehyde and ammonia The carhoxaldehydc may be an alkyl carboxaldehyde, such as acctaldehydc or propionaldehydc, an arylcarboxaldehyde, such as henzenecarhoxaldehyde, a substituted arylcarboxalde hyde, such as o-cyanobenzenecarboxaldehyde. p-nitrobenzenecarboxaldehyde, p-sulfamoylbenzenecarboxaldehyde, and p-methoxybenzenecarboxaldehyde, or a heteroarylcarboxaldehyde, such as pyridinecarboxaldehyde, quinolinecarboxaldehyde, thiazolecarboxaldehyde', thiophenecarboxaldehyde, or cinnolinecarboxaldehyde.

The overall reaction scheme can be depicted as follows:

mild base 0 N & 346110 NH; FaC- -CHBI2 G F; N R2 I (III) (II) For example, where R in Formula ll is 4-pyridyl, the trifluoromethylimidazole compound is prepared by reacting about equimolar amounts of, for example, 1,]- dibromo-3,3,3-triflu0roacetone with 4- pyridinecarboxaldehyde and ammonia. In general, the

trifluoroacetone compound is first added to a solution containing a slight excess ofa mild base; any mild base, such as sodium acetate or potassium carbonate, may be employed. Hydroxylic solvents such as aqueous ethanol or water may be employed, but the reaction is generally carried out in water. The solution is heated for from about minutes to about 2 hours at a temperature between room temperature and about 150C.; the preferred temperature range, however, is about 80I00C. The reaction is then cooled, preferably to ice bath temperatures. The cooled solution is then added to a solution of the carboxaldehyde in a suitable solvent. Water-miscible solvents such as methanol, ethanol, dioxane or tetrahydrofuran may be employed. Ammonia is then added to the reaction mixture, and the mixture is allowed to stand at about room temperature for from about 1 hours. The ammonia may be added as a gas or alternatively as an aqueous or alcoholic solution. The trifluoromethylimidazole compound is then obtained by techniques known in the art.

For example, concentration of the reaction mixture will generally yield the trifluoromethylimidazole compound as a solid residue. The product can be purified by recrystallization from an appropriate solvent such as water, acetonitrile or benzenehexane.

Those compounds wherein the substituent on the phenyl ring is amino can be prepared from the 2- phenyltrifluoromethylimidazole compounds having a loweralkanoylamino group as the substituent on the phenyl ring. The reaction is carried out by first suspending a loweralkanoylaminophenyltrifluoromethylimidazole compound such as, for example, Z-(pacetylaminophenyl)-4(5)-trifluoromethylimidazole, in a dilute mineral acid such as, for example, 10 percent hydrochloric acid, and the acid suspension is heated for from about l5 minutesto about two hours at a temperature of about 50 150C. The preferred temperature range is 75 100C. The aminophenyltrifluoromethylimidazole compound is obtained by neutralizing the acid solution with a mild alkali such as sodium bicarbonate and collecting the resulting precipitate by techniques known in the art. Alternatively, the 2-aminophenyltrifluoromethylimidazole compounds can be obtained by catalytic reduction of the corresponding nitro compounds.

Those compounds wherein the substituent in the 2 position is the residue formed by reaction of a cyclic anhydride with an amine can be prepared from a 2- aminophenyl-4(5)-trifluoromethylimidazole by reacting the 2-aminophenyl-4(5)-trifluoromethylimidazole compound with maleic anhydride in a suitable solvent such as, for example. diethyl ether. The reaction is generally carried out at room temperature, buttemperatures between room temperature and about 50C. may be employed. The reaction product generally crystallizes from the reaction mixture and is collected and purifled by techniques known in the art.

The compounds of Formula I wherein R is lower alkyl can be prepared byreacting 21 4(5)- trifluorometh ylimidazolesuch as, for example, 2-(pfluorophenyl)-4(5)-trifluoromethylimidazole, with an alkylating agent such as diazomethane or with a dilower alkylsulfate such as dimethylsulfate in a suitable solvent such as acetic acid or methanol, or witha lower alkylhalide such as methyliodide in a suitable solvent, as, for example, in a mixture of toluene and dimethyl sulfoxide. The alkylationmay be carriedout at room temperature, but it is preferred to carry out the reaction at elevated temperatures from about l0l50C. for from about 1-30 hours. The reflux temperature of the solvent is a convenient temperature for the alkylation step. The alkylated trifluoromethylimidazole compound is then isolated by techniques known in the art. For example when the alkylating agent is a di-lower alkylsulfate, one such method of isolation consists in removing the solvent and triturating the residue with dilute alkali, such as ammonium hydroxide, followed by the taking up of the product in a suitable solvent such as hexane. The alkylated trifluoromethylimidazole compound is then obtained upon removal of the solvent.

Those compounds of Formula I where R is hydroxylower alkyl can be prepared by reacting a l,2-epoxy or l,3-epoxy loweralkane, such as, for example, 1,2- epoxyethane and l,3-epoxypropane, with about an equimolar mixture of a 4-(5 )-trifluoromethylimidazole compound and a Lewis acid, in a suitable solvent, such as acetic acid or methyl alcohol. As the ,Lewis acid, compounds such as boron trifluoride and sulfur trioxide can be employed. Generally, a molar excess of the epoxide is employed, and the reaction is-carried out at a temperature between about C. and 60C. The

preferred reaction temperature, however, is between about 20C. and 50C. The epoxide is usually added gradually at such a rate as to keep the reaction within the desired temperature range. Depending upon the temperature range employed, the reaction mixture is allowed to stand from about 10 minutes to about 18 hours. The hydroxy-alkylated 4( 5 trifluoromethylimidazole compound is then isolated by techniques known in the art.

In order to prepare those compounds of Formula I wherein R, is hydroxyloweralkyl, it may be necessary in some instances to protect the compounds having substituents which are sensitive to the alkylating agents in order to obtain a good yield.

Where the substituent on the Z-phenyl substituent is a carboxy group, the carboxy group can be protected by converting it to the ester. Where the phenyl substituent is substituted with an amino group or a monoalkyl amino group, the amine function can be protected by acylation with, for example, an acetyl group. Where the substituent on the Z-phenyl substituent is a diamino group, the amino function can be protected by converting it to an N-oxide. Where the substituent on the 2- phenyl substituent is a sulfamoyl group, the sulfamoyl group may also be alkylated. The sulfamoyl group can be regenerated by reaction with chlorosulfonic acid, followed by reaction of the resulting sulfonyl chloride compound with ammonia. In those cases where a protecting group is necessary, the protecting group is removed by techniques known in the art. Y

The quaternary salts which fall within the scope of the present invention have as the substituent in the 2 position a nitrogen-containing aromatic ring such as a pyridine or quinoline ring. These quaternary salts can be prepared by reacting the 2-substituted 4(5)- trifluoromethylimidazole compound with an alkyl iodide such as, for example, methyl iodide or ethyl iodide in a suitable solvent, such as methanol, ethanol, or dimethylformamide. The reaction-is generally carried out at room temperature, and the quaternary salt is usually obtained as a solid upon removal of the solvent. The

following are examples of quaternary salts which are within the scope of the present invention: N-methyl-4-[4( )-trifluoromethyl-2- imidazolyllpyridinium iodide N-ethyl-4-{ 4-( 5 )-trifluoromethyl-2- imidazolyl]quinolinium iodide N-methyl-2-( l-ethyI-4-trifluoromethyl-2- imidazolyl)pyridinium iodide, and

N-methyl-3-[ I-( 2-hydroxyethyl-4-trifluoromethyl2- imidazolyl)]pyridinium iodide.

The metal salts of the 4( 5-trifluoromethylimidazoles, that is, those compounds where R, in Formula I is hydrogen, can be prepared by methods known in the art. For example, the sodium or potassium salt can be prepared by addition of an equivalent amount of sodium or potassium hydroxide to a solution of the trifluoromethylimidazole compound. The salt is then obtained by concentrating the reaction mixture.

The acid addition salts of the 4(5)- trifluoromethylimidazoles having in the 2-position a heterocyclic ring containing at least one nitrogen atom can be prepared by any of the known methods for preparing acid addition salts of amines.

The 4(5)-trifluoromethylimidazoles which are the subject of this invention inhibit the action of the enzyme xanthine oxidase resulting in a significant decrease in the concentration of uric acid in the blood and urine and are, therefore, capable of aborting attacks of gout.

In addition, as indicated above, some of the 4(5)- trifluoromethylimidazoles, such as 2-(3-pyridyl)-4(5)- trifluoromethylimidazole and 2-(4-pyridyl)-4(5)- trifluoromethylimidazole exhibit hypotensive activity and also inhibit gastric secretion.

For testing purposes, xanthine oxidase obtained from milk may be employed to demonstrate the ability of the 4(5)-trifluoromethylimidazoles to inhibit the enzyme. The general procedure is to employ a 5-10 unit suspension of the enzyme per milliliter of 60 percent saturated ammonium sulfate of the enzyme; 1 unit of such a suspension converts lu mole of xanthine t0 uric acid per minute. Generally, for a l-day assay, about 0.05 ml. of enzyme is diluted with about 3 ml. of buffer. As the buffer, tris buffer (0.05 mole) pH 7.4 may be employed. The inhibitor to be tested is dissolved in buffer or a suitable solvent, such as dimethylsulfoxide; the same solvent is used to dilute the solution. The buffer, hypoxanthine and solvent are placed in a cell, and the resulting solution is shaken to absorb air. The diluted enzyme solution is then added, and the rate of increase in absorbance at 290 my. is noted with a recording spectrophotometer. Generally, sufficient enzyme is employed to give about 0.1 absorbance units change per minute, and sufficient inhibitor is used to give 30-70 percent inhibition. The #M concentration of inhibitor necessary for 50 percent inhibition (V /V, 2) is determined by plotting V /V against I, where V velocity without inhibitor. V, velocity with inhibitor. and I inhibitor concentration. The activity of the tested compound is expressed in terms of percent inhibition.

The therapeutically active trifluoromethylimidazoles can be administered as the active ingredient in association with a pharmaceutically acceptable carrier in the form of tablets. elixirs, capsules, and the like. These 6 preparations may be made by any of the known pharmaceutical methods. For example, in tablet form, they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, gums, starches, and sugars. They may also be incorporated into a gelatin capsule or formulated into elixirs which have the advantage of being susceptible to manipulations in flavor by the addition of standard natural or synthetic flavoring materials. The compound is generally administered in compositions which are so positioned as to afford a unit dosage of about 30 mg. to 1.5 gm. per day. The preferred dosage level, however, is about I00-800 mg. per day.

The following examples serve to illustrate typical tablet, capsule, and elixir formulations incorporating the therapeutically active 4(5)-trifluoromethylimidazoles of this invention:

FORMULATION I: COMPRESSED TABLET COMPRISING 05 OF ACTIVE INGREDIENT The 2-(4-pyridyl)-4(5)-trifluoromethylimidazole is granulated with the starch paste and while moist passed through a No. I4 screen, dried at 45C. for 20 hours, and then passed 3 times through a No. 14 screen. The starch is then passed through a No. bolting cloth onto the granulation, and all ingredients are blended thoroughly. The magnesium stearate is passed through a No. 90 bolting cloth onto the granulation, and these ingredients are blended, after which the granulation is compressed into tablets using a 14/32 inch flat, bevelled. scored punch having a thickness of 0205:0005 inch yielding L000 tablets each weighing 0.543 grams.

Blend lactose, talc and the 2-(6-quinolyI)-4(5)- trifluoromethylimidazole in suitable blending equipment, and encapsulate into a No. 2 capsule at a target weight of 350 mg.

FORMULATION Ill: LIQUID SUSPENSION FORMULA Ingredient Amount git.

Veegum HN'.

Water 2 Methyl Paraben Ltp-carboxphenyD-Mfi- 5 trifluoromethylimidazole Kaolin Flavor Glycerin. 9.5 to 1 liter Suspend Veegum in water with vigorous agitation, acid methyl paraben and allow to stand overnight to ensure complete hydration of Veegum. In separate vessel suspend 2-( p-carboxyphenyl )-4( 5 trifluoromethylimidazole in about 750 cc. of glycerol.

Add kaolin and stir until homogeneous. Slowly add EXAMPLE 1 2-( 4-Pyridyl)-4( )-Trifluoromethylimidazole Sodium acetate trihydrate l 1.6 grams, 0.084 mole) is dissolved in ml. of water. and l.l-dibromo-3,3,3- l5 trifluoroacetonel l 1.6 grams, 0.042 mole) is added to the resulting aqueous solution. The solution is heated for 30 minutes at 100C. and is then cooled in an ice bath. The cooled solution is added to a solution of 4- methanol (200 ml.). Concentrated aqueous ammonia ml.) is added to the alcoholic solution, and the reaction mixture is allowed to stand for 5 hours at room temperature. The mixture is then concentrated to about ml., and the product separates from the solution as an oil which solidifies on standing. Upon recrystallization from water, there is obtained 2-(4-pyridyl)- 4(5 )-trifluoromethylimidazole, m.p. l56-l 57.5C.

When in the above procedure 3- pyridinecarboxaldehyde is employed in place of 4- pyridinecarboxaldehyde, there is obtained 2-(3- pyridyl )-4( 5 )-trifluoromethylimidazole, m.p. 228228.5C.

When in the above procedure 2- pyridinecarboxaldehyde is employed in place of 4- pyridinecarboxaldehyde, there is obtained 2-(2- pyridyl )-4( 5 )-trifluoromethylimidazole, m.p. l56-l57.5C.

The procedure described in Example 1 is used to prepyridinecarboxaldehyde (4.7 grams, 0.044 mole) in 20 pure the following compounds (Examples 2 .33A):

EXAMPLES 2 33A Ex. (0.044 mole) No. Starting Material Product Melting Point 2 Z-quinoline- 2-(2-quinolyl)-4(5)- carboxaldehyde trifluoromethylimidazole l 565-! 58C. 3 4-thiazole- 2-(4-thiazolyl)- 235236C.

carboxaldehyde 4( S )-trifluoromethylimidazole 4 Z-furan- 2-(2-furyl)-4(5)-tril92-l93.5C.

carboxaldehyde fluoromethylimidazole 5 isobutyraldehyde 2-isopropyl-4(5 )-tri- 201 .5-202.5C.

fluoromethylimidazole 6 propionaldehyde 2'ethyl-4(5 )trifluorol l5-l22C.

methylimidazole 7 acetaldehyde 2-m e.thyl-4( 5 )-trifluorol6 1 l 65C.

methylimidazole 8 formaldehyde 4(5)-trifluoromethyl- 148.5l49.5C.

' imidazole 9 l-naphthylene- 2-( l -naphthyl)-4( 5 249-250C.

carboxyaldehyde trifluoromethylimidazole l0 Z-naphthylene- 2-( 2-naphthyl)-4( 5 2 l 0-2l lC.

carboxaldehyde trifluoromethylimidazole l l Z-thiophene- 2-(2-thienyl)-4(5)-tri- 21 l.52l2C.

carboxaldehyde fluoromethylimidazole l2 p-cyanobenzene- 2-( p-cyanophenyl )-4( 5 207-208C.

carboxaldehyde trifluoromethylimidazole l3 p-fluorobenzene- 2-( p-fluorophenyl )-4( 5 206.5207.5C.

carboxaldehyde trifluoromethylimidazole l4 o-chlorobenzcne- 2-(o-chlorophenyl)-4(5)- l65l67C.

carboxaldehyde trifluoromcthylimidazolc l5 m-chlorobenzene- 2-(m-chlorophenyl)-4(5)- l86.5|87.5C.

carboxaldehyde trifluoromethylimidazole l6 p-chlorobenzenc- 2-(p-chlorophcnyl)-4(5)- 226228C.

carboxaldehyde lrifluoromethylimidazolc l7 3,4-dichloro- 2-( 3,4-dichlorophenyl 2 l 2.5-2 1 135C.

benzcnecarbox- 4( 5 )-trifluoromethylaldehyde imidazole l8 2.4-dichloro- 2-( ZA-dichlorophcnyl 19 l 493C.

benzene 4( 5 )-trifluoromethylcarboxaldehyde imidazole l9 p-carboxybenzcne- 2-(p-carhoxyphenyh- 287C. dec.

carboxaldchyde 4(5)-trifluoromethylimidazole 20 p-mcthylbenzcne- 2-(p-mcthylphenyl)-4(5)- 2l8220C.

carboxaldehyde trifluommethylimidazole 21 m-methylbcnzcne- 2-(m-methylphcnyl)-4(5 ll9lC.

carboxaldehyde lrifluoromethylimidazolc 22 p-sulfamoyl- 2-(p-sulfamoylphcnyl)- 290C. dec.

benzenecarbox- 4(5)-trifluoromcthylaldehyde imidazolc 23 S-indane 2(5-indanyl)-4(5 2l l2l3C.

carboxaldehyde trifluoromethylimidazolc 24 3-cinnoline- 2-(3-cinnolyl)-4(5)- 275-277C.

carboxaldchyde trifluoromethylimidazolc 25 bcnzenecarhox- 2-phcnyl-4(5)-tri- 208-209.5C'.

aldehyde fluoromcthylimidazolc 26 p-methoxybcnzcnc- 2-(p-mcthoxyphenyl)- 204206C.

carboxaldehyde 4(5)-trifluoromethylimiduzole 27 p-acetylamino- 25 273-274C.

henzenccarhnxaldehyde .trifluoromethylimidazole (4 grams) is suspended in 10 percent hydrochloric acid (85 ml. and the suspension is heated at lC. for about 30 minutes. The resulting solution is filtered. and the filtrate is neutralized with aqueous sodium bicarbonate. The crude product settles out of the neutral solution. and after recrystallization from benzene, 2-(p-aminophenyl)-4(5)- trifluoromethylimidazole, m.p. 2l4.52l5C., is obtained.

EXAMPLE 35 p-[4( )-Trifluoromethyl-2-lmidazolyl -Maleanilic Acid 2-( p-Aminophenyl )-4( 5 )-trifl uoromethylimidazole (1.13 grams, 0.005 mole) is dissolved in ether (150 ml.). A solution of maleic anhydride (0.5 grams, 0.005 mole) in ether (501111.) is added to the resulting solution, and the resulting solution is allowed to stand for 1 hour at room temperature. The product settles out of solution and is collected by filtration. Additional crystals are obtained upon concentration of the ether filtrate. The combined solids are dissolved in 2.5 percent aqueous sodium hydroxide and re-precipitated by the addition of hydrochloric acid. Upon filtration and recrystallization from 70 percent ethanol, there is obtained ,p-[ 4( 5 )-trifluoromethyl-2-imidazolyl maleanilic acid, m.p. 235.5237C.

EXAMPLE 36 2-( 3 ,4-Dimethoxyphenyl)-4( 5 Trifluoromethylimidazole Sodium acetate trihydrate (0.084 mole) is dissolved in 50 ml. of water, and trifluoroacetone (0.042 mole) is added to the resulting aqueous solution. The solution is heated for minutes at 95C. and is then cooled in an ice bath. The cooled solution is added to a solution of 3.4-dimethoxybenzenecarboxaldehyde (0.044 mole) in methanol (174 ml.). Concentrated aqueous ammonia (50 ml.) is

EXAMPLES 2 33A Ex. (0.044 mole) No. Starting Material Product Melting Point 28 p-nitrohcnzcnc- Z-(p-nitrophcnyhl95-l96.5C.

carhoxuldchydc 4( 5 )-trifluoromcthylimidazolc 29 p-dimcthyl- Z-t p-dimcthylamino- 264-265C.

aminohcnzcncphcnyl )4( 5 )-tricarboxaldchydc fluoromcthylimidazole 3O 3 ,4-mcthylcnc- Z-t 3,4-methylcncdioxy- 204-207C.

dioxybcm'cncphcnyl )-4( 5 )-trifl uorocarboxaldchyde mcthylimidazole 3i m-brompbcnzcne- 2-(m-bromophcnyl)- l89"C.

carboxaldchydc 4( 5 )-trifluoromcthylimidazole 32 3 methoxy- 2 l2(5-mcthoxy- 2l8-220C. pyrazine pyruzinyl ]-4( 5 carhoxaldchydc trifluoromcthylimidazolc 33 p-isopropyl- 2-( p-isopropyl- 249C.

' benzcnccarboxphcnyl)-4(5)-trialdehyde fluoromethylimidazolc 33A fi-quinolinecarbox- 2-( 6-quinolyl)-4(5 254.5255C.

aldchydc trifluoromethylimidazole EXAMPLE 34 added to the alcoholic solution. and the reaction mix ture is allowed to stand for 5 hours at room temperature. The mixture is then concentrated to about ml.. and the product separates from the solution as an oil which solidifies on standing. Upon recrystallization from alcohol, there is obtained 243.4- dimethoxyphenyl )-4( 5 )-trifluoromethylimidazole, m .p. l88l90C.

When in the above procedure p-N.N- dimethylsulfamoylbenzenecarboxaldehyde and pmethylaminobenzenecarboxaldehyde are employed in place of 3,4-dimethoxybenzenecarboxaldehyde, there are obtained 2-(p-N,N-dimethylsulfamoylphenyl)- 4( 5 )-trifluoromethylimidazole and 2-( pmethylaminophenyl )-4( 5 l-trifiuoromethylimidazole, respectively.

EXAMPLE 37 When in Example 1 2,6-dirnethyl-4- pyridinecarboxaldehyde, 4,6-dimethyl-2- pyridinecarboxaldehyde, and 2-methyl-3- pyridinecarboxaldehyde are employed in place of 4- pyridinecarboxaldehyde, there are obtained 2-(2,6- dimethyl-4-pyridyl )-4( 5 l-trifluoromethylimidazole, 2- (4,6-dimethyl-2-pyridyl )-4( 5 trifluoromethylimidazole, and 2-(2-methyl-3-pyridyl)- 4( 5 l-trifluoromethylimidazole, respectively.

EXAMPLE 38 N-Methyl-4l 4( 5 l-Trifluoromethyl-Z-lmidazolyl Pyridinium lodide To a solution of 2-(4-pyridyl )-4( 5 trifluoromethylimidazole (2.13 grams, 0.01 mole) in methanol (50 ml.) is added methyl iodide (7 grams, 0.05 mole). The resulting solution is allowed to stand for 24 hours at room temperature, and the solvent is concentrated until a solid is obtained. The solid is washed with diethyl ether and is collected by filtration, yielding 2.4 grams of crude product. Upon recrystallization from isopropyl alcohol. N-methyl-4[4(S)- trifluoromethyl-2-imidazolyl]-pyridinium iodide is obtained, m.p. 230-232C., dec.

When in the above procedure ethyl iodide is employed in place of methyl iodide, N-ethyl-4[4(5)- trifluoromethyl-2-imidazolyll-pyridinium iodide is obtained.

EXAMPLE 39 2-(p-Fluorophenyl)-1-Methyl-4(and 5 )-Trifluoromethylimidazole Dimethylsulfate (0.63 grams, 0.005 mole) is added to a solution of 2-(p-fluorophenyl )-4(5 trifluoromethylimidazole (1.1 grams, 0.005 mole) in acetic acid ml.), and the reaction mixture is refluxed overnight. After 17 hours at reflux, additional dimethylsulfate (0.63 grams, 0.005 mole) is added, and the solution is heated at reflux for an additional 5 hours. The acetic acid is removed in vacuo, and the resulting residue is triturated with dilute ammonium hydroxide, water, and then with hexane. The hexane extract is concentrated to a solid residue and is sublimed to yield 200 mg. of product. Upon recrystallization from hexane, 2-(p-fluorophenyl)-l-methyl-4(and 5)- trifluoromethylimidazole are obtained, m.p. 8l84.5C. Thin layer chromatography and VPC indi- 'cate the presence of two isomeric components.

When in the above procedure diethylsulfate is employed in place of dimethylsulfate, 2-(p-fluorophenyl)- l-ethyl-4(and 5)-trifluoromethylimidazole are obtained.

EXAMPLE 40 1-( Z-Hydroxyethyl )-5-Trifluoromethylimidazole 4(5)-Trifluoromethylimidazole (0.062 mole) is dissolved in 150 ml. of acetic acid, and boron trifluoride etherate (0.057 mole) is added to the resulting solution. Ethylene oxide (0.35 mole) in 20 ml. of hexane is added dropwise with stirring during one hour to the reaction mixture while maintaining the temperature of the reaction mixture at 3235C. with a water bath. After the addition of. ethylene oxide is complete, the mixture is concentrated in vacuo to about 20 ml., and the residue is diluted with 50 ml. of water neutralized to pH 7 with aqueous sodium hydroxide and extracted with 100 mlqof ethyl acetate. The extract is dried over magnesium sulfate and filtered. Upon removal of the solvent, l-(2-hydroxyethyl)-5- trifluoromethylimidazole is obtained.

. When in the above procedure 2-(o-chlorophenyl)-4- (5 )-trifluoromethylimidazole and 2-(p-methylphenyl 4(5)-trifluoromethylimidazole are employed in place of 4(5)-trifluoromethylimidazole, thereare obtained l-( Z-hydroxyethyl )-.2-(o-c hlorophenyl )-5- trifluoromethylimidazole and l-( 2-hydroxyethyl)-2-(pmethylphenyl )-5-trifluoromethylirnidazole, respectively.

EXAMPLE 41 2-Pyrazinyl-4( 5 )-Trifluoromethylimidazole Sodium acetate trihydrate (5.8 g., 0.042 mole) is dissolved in 20 ml. of water, andl,l-dibromo-3,3,3- trifluoroacetone (5.8 g., 0.021 mole) is added to the resulting aqueous solution. The solution is heated for 30 minutes at 100C, and then cooled in an ice bath.

The cooled solution is added to a solution of 2- pyrazinecarboxaldehyde (2.3 g., 0.022 mole) in methanol (100 ml.). Concentrated aqueous ammonia ml.) is added to the alcoholic solution, and the reaction 18 mixture is allowed to stand for 5 hours at room temperature. The mixture is then concentrated to about 35 ml., and the product separates from the solution as an oil which solidifies on standing. Upon recrystallization from acetonitrile, there is obtained 2-pyrazinyl-4(5)- trifluoromethylimidazole, m.p. 237-238C.

EXAMPLE 42 2-(p-Methylsulfonamidophenyl)-4- Trifluoromethylimidazole To a solution of Z-(p-aminophenyl )-4- trifluoromethylimidazole (3.0 g.) in acetone (50 ml.) and triethylamine (2.7 g.) is added methanesulfonyl chloride 1.5 g.). After refluxing for four hours, a second portion of methanesulfonyl chloride (1.5 g.) is added. Reflux is continued 20 hours, a third portion of methanesulfonyl chloride (1.5. g.) is added and reflux continued another four hours. The reaction mixture is filtered and concentrated to an oil which, upon trituration with water, affords a solid. After chromatography on silica gel and recrystallization from a mixture of acetonitrile and .water 1 .3 g. of 2-( pmethylsulfonarnidophenyl )-4- trifluoromethyli midazole, m.p. 253255C. is obtained.

EXAMPLE 43 l,4-Bis( 4-Trifluoromethyl-2-Imidazolyl )Benzene To a solution of sodium acetate trihydrate (5.9 g.) in water (20 ml.) is added l,l-dibromo-3,3,3- t'rifluoroacetone (5.9 g., 0.022 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of terephthalaldehyde (l.34 g., 0.01 mole) in methanol-( ml.) and concentrated aqueous ammonia (25 ml.'). The reaction mixture is allowed to stand for four hours at room temperature. The reaction mixtureis concentrated under reduced pressure; water is added andthe resulting solid is filtered. After recrystallization from a mixture of methanol and water 450 mg. of l,4-bis(4- trifluoromethyl-Z-imidazolyl)benzene, mp. 325C, is obtained.

EXAMPLE 44 2-( l Dimethylamino-2-Methyl-2-Propyl )-4- Trifluoromethylimidazole To a solution of sodiumacetate trihydrate l 1.8 g.)

in water (40 ml.) is added l,l-dibromo -3,3,3- trifluoroacetone (l 1.8 g., 0.044 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solutionis added to a solution of 2,2- dimethyl-3-dimethylaminopropionaldehyde (5.6 g., 0.044 mole) in methanol ml.) and concentrated aqueous ammonia (50 ml. The reaction mixture is allowed to stand for 3.5 hours at room temperature and the reaction mixture is then concentrated under reduced pressure to yield the semi-solid which is recrystallized from hexane and then sublimedto yield 3 g. of 2-( l-dimethylamino-Z-methyl-2-propyl )-4- trifluoromethylimidazole, m.p., l33l35C.

EXAMPLE 45 2-( m-Methoxymethoxyphenyl )-4- Trifluoromethylimidazole To a solution of sodium acetate trihydrate (11.8 g.) in water (40 ml.) is added l,l-dibromo-3,3,3-

trifluoroacetone (11.8 g., 0.044 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of m-methoxymethoxybenzaldehyde (7.2 g., 0.004 mole) in methanol (200 ml.) and concentrated aqueous ammonia (50 ml.). The reaction mixture is allowed to stand 4.5 hours at room temperature. The reaction mixture is concentrated under reduced pressure to yield an oilwhich solidifies. After recrystallization from a mixture of benzene and hexane 4.1 g. of 2-(mmethoxymethoxyphenyl )-4-trifluoromethylimidazole, m.p., 155.515 7.5C. is obtained.

EXAMPLE 46 2-( p-Diethylaminoethoxyphenyl )-4- Trifluoromethylimidazole To a solution of sodium acetate trihydrate (5.9 g.) in water (20 ml.) is added l,l-dibromo-3,3,3- trifluoroacetone (5.9 g., 0.022 mole). The solution is heated 60 minutes at steam bath temperature and then cooled. The solution is added to a solution of pdiethylaminoethoxybenzaldehyde (2.4 g., 0.01 1 mole) in methanol (100 ml.) and concentrated aqueous ammonia (25 ml.). The reaction mixture is allowed to stand 4 hours at room temperature. The reaction mixture is concentrated under reduced pressure and extracted with ether. The ether extract is dried and concentrated to an oil which after chromatography on silica gel and recrystallization form a mixture of ethanol and water gave 0.6 g. of 2-( pdiethylaminoethoxyphenyl )-4- trifluoromethylimidazole, m.p., 145146C.

EXAMPLE 47 2-(3-Pyridyl-1-Oxide)-4-Trifluoromethylimidazole To a solution of 2-( 3-pyridyl )-4- trifluoromethylimidazole 1.0 g.) in acetic acid ml.) is added 30 percent hydrogen peroxide 1 g.). The reaction mixture is heated overnight at steam bath temperature and is poured onto 10 ml. of saturated aqueous sodium bicarbonate solution. The mixture is neutralized with 40 percent aqueous sodium hydroxide and the resulting solid is filtered and recrystallized from water to yield 250 mg. of 2-(3-pyridyl-1-oxide)-4- trifluoromethylimidazole, m.p. 224225C.

By substituting 2-(4-pyridyl)-4- trill uoromethylimidazole for 2-( 3-pyridyl )-4- trifluorometh'ylimidazole in the above method and otherwise following the procedure described therein there is thus obtained 2-(4-pyridyl-1-oxide)-4- trifluoromethylimidazole, mp. 242C.

- EXAMPLE 48 2-( l-Benzyl-4-Pyrazo1yl)-4-Trifluoromethylimidazole 20 1-benzyl-4-pyrazolyl)-4-trifluoromethylimidazole, m.p., 157159.5C., is obtained.

EXAMPLE 49 2-Diphenylmethyl-4-Trifluoromethylimidazole To a solution of sodium acetate trihydrate-( 5.8 g.) in water (20 ml.) is added l.l-dibromo-3,3.3- trifluoroacetone (5.9 g., 0.022 mole). The solution is heated 60 minutes at steam bath temperature and then cooled. The solution is added to a solution of 1,1 diphenylacetaldehyde (4.3 g.. 0.022 mole) in methanol (150 ml.) and concentrated aqueous ammonia (25 ml.). The reaction mixture is allowed to stand for five hours at room temperature. The reaction mixture is concentrated under reduced pressure to half volume. water is added and the solid removed by filtration. After recrystallization from a mixture of acetonitrile and water 2.0g. of Z-diphenylmethylltrifluoromethylimidazole, mp. 23023lC., is obtained.

EXAMPLE 50 2-( 1-Phenyl-4-Pyrazolyl )-4-Trifluoromethylimidazole To a solution of sodium acetate trihydrate (2.9 g.) in water (10 ml.) is added 1,1-dibromo-3.3.3- trifluoroacetone (2.9 g., 0.01 1 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of l-phenyl- 4-pyrazolecarboxaldehyde 1.7 g., 0.01 mole) in methanol (50 ml.) and concentrated aqueous ammonia 15 ml.). The reaction mixture is allowed to stand for 4 hours at room temperature. The mixture is concentrated under reduced pressure and the resulting solid is filtered. After recrystallization from acetonitrile 0.6 g. of 2-(1-phenyl-4-pyrazolyl) 4- trifluoromethylimidazole. m.p.. 205206C., is obtained.

EXAMPLE 5 1 2-( 1-Methyl-4-Pyrazolyl)-4-Trifluoromethylimidazole To a solution of sodium acetate trihydrate (2.7 g.) in water (10 ml.) is added l.l-dibromo-3,3,3- trifluoroacetone (2.7 g.. 0.01 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of l-methyl- 4-pyrazolecarboxaldehyde 1.1 g., 0.01 mole) in methanol (50 ml.) and concentrated aqueous ammonia 15 ml.). The reaction mixture is allowed to stand for 4.5 hours at room temperature. The mixture is concentrated and the resulting product is chromatographed on silica gel and recrystallized from water to yield mg. of 2-( 1-rnethyl-4-pyrazolyl )-4-4- trifluoromethylimidazole. m.p., 206-207C.

EXAMPLE S2 2-[ 1-( p-Chlorophenyl )-4-Pyrazolyl ]-4- Trifluoromethylimidazole To a solution of sodium acetate tn'hydrate 10.0 g.) in water (35 ml.) is added 1,1-dibromo-3,3,3- trifluoroacetone 10.0 g.. 0.037 mole). The solution is heated 30 minutes at steam bath temperature and then cooled. The solution is added to a solution of l-(pchlorophenyl) pyrazole-4-carboxaldehyde (7.8 g., 0.038 mole) in methanol ml.) and concentrated aqueous ammonia (43 ml.) The reaction mixture is allowed to stand 4.5 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the resulting product is recrystallized from a mixture of water and acetonitrile to yield 2.64 g. of 2-[1- (p-chlorophenyl)-4-pyrazolyl]-4- trifiuoromethylimidazole, m.p., 233-235C.

EXAMPLE 53 2-( 2-Methyl-4-Pyridyl )-4-Trifluoromethylimidazole To a solution of sodium acetate trihydrate (5.8 g.) in water (20 ml.) is added l,l-dibromo-3,3,3- trifluoroacetone (5.9 g., 0.022 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of 2- methylisonicotinaldehyde (2.4 g., 0.02 mole) in methanol (100 ml.) and concentrated aqueous ammonia (25 ml.). The reaction mixture is allowed to stand 4.5 hours at room temperature. The reaction mixture is concentrated under reduced pressure; an oil separates and solidifies and this is filtered (0.6 g.) after recrystallization from a mixture of water and ethanol to afford 2-(2- methyl-4-pyridyl)-4-trifluoromethylimidazole, m.p., 195-197C.

7 EXAMPLE 54 2-( 6-Methyl-3-Pyridyl )-4-Trifluoromethylimidazole EXAMPLE 55 1 -Methyl-2-( 3-Pyridyl )-4-Trifluoromethylimidazole To 2-(3-pyridyl)-4(5 )-trifluoromethylimidazole (2.1 g.) in 15 ml. of toluene dimethylsulfoxide (9:1 is added 57 percent sodium hydride in mineral oil (0.46 g.). The mixture is stirred for 15 minutes at room temperature; methyl iodide 1.6 g.) is added and stirring is continued for three hours. The reaction mixture is filtered; the solid portion is washed with benzene and the combined filtrate concentrated to an oil. The oil is distilled in an evaporative still at 165C. and 0.03 mm. pressure. The distillate is chromatographed on silica gel to yield essentially pure 1-methyl-2-(3-pyridyl)-4- trifiuoromethylimidazole which is redistilled in an evaporative still at 165C. and 0.3 mm. to afford 0.8 g. of product.

- Analysis for C|H3F3N3 Calculated: N. 18.50; C, 52.86; H, 3.55 Found: N, 18.25; C, 52.92; H, 3.65

EXAMPLE 56 1-Methyl 2-(Z-Pyridyl)-4-Trifiuoromethylimidazole I To 2-(2-pyridyl)-4(5)-trifiuoromethylimidazole (2.1 g.) in ml. of toluene-dimethylsulfoxide (9:1') is added 57 percent sodium hydride in mineral oil. After stirring for 15 minutes at room temperature, methyl iodide (1.6 g.) is added. The reaction mixture is stirred four hours and filtered; the solid portion is washed with benzene and the combined filtrates are concentrated to i an oil which solidifies. After recrystallization from hexane 250 mg. of 1-methyl-2-( 2-pyridyl)-4- trifiuoromethylimidazole, m.p., 78-80C., is obtained.

AnalySiS f0! C10H8F3N3 Calculated: N, 18.50; C, 52.86; H, 3.55 Found: N, 18.36; C, 52.77; H, 3.58

EXAMPLE 57 1-Methyl-2-Phenyl-4-Trifiuoromethylimidazole By substituting an equivalent amount of 2-phenyl-4- trifiuoromethylimidazole for the 2-(2-pyridyl)4(5)- trifiuoromethylimidazole of Example 57 and following substantially the procedure described therein there is obtained 250 mg. of 1-methyl-2-pheny1-4- trifiuoromethylimidazole, m.p., 61.5-62.5C.

Calculated: C, 58.41; H, 4.01; N, 12.39

Found: C, 58.82; H, 4.02; N, 12.44

EXAMPLE 58 1-Ethyl-2-Phenyl-4-Trifluoromethylimidazole By substituting equivalent amounts of ethyl iodide and 2-phenyl-4-trifluoromethylimidazole for the methyl iodide and I 2-(2-pyridyl)-4(5)- trifiuoromethylimidazole of Example 57 and following substantially the procedure described therein there is obtained 1-ethy1-2-phenyl-4-trifluoromethy1imidazo1e, b.p., l60l65C. 0.5 mm.

Calculated: C, 59.97; H, 4.62; N, l 1.66

Found: C, 59.91; H, 4.53; N, 11.45

EXAMPLE 59 1-Methyl-2-.( 4-Pyridyl )-4-Trifluoromethylimidazole By substituting an equivalent amount of 2-(4- pyridyl)-4(5)-trifluoromethylimidazole for the 2-(2- pyridyl)4(5)-trifluoromethylimidazole of Example 57 and following substantially the procedure described therein there is obtained 0.75 g. of 1-methyl-2-(4- pyridyl)-4-trifluoromethylimidazole, m.p., 125-126.5C.

EXAMPLE 60 l-Methyl-2-Phenyl-S-Trifluoromethylimidazole To a solution of 2-phenyl-4(5)- trifiuoromethylimidazole (4.2 g.) in acetic acid (40 ml.) is added dimethylsulfate (5.0 g.) and the mixture is heated at reflux for 16 hours. Dimethylsulfate (2.5 g.) is added and reflux is continued for 8 hours. The reaction mixture is concentrated to an oil and saturated aqueous sodium bicarbonate is added whereupon a solid separates. The solid is treated with hexane and insoluble material is removed. The hexane solution is then concentrated to a solid and chromatographed and EXAMPLE 61 1-Methyl-2-( p-Chlorophenyl Trifluoromethylimidazole To a solution of 2-(p-chlorophenyl)-4(5)- trifluoromethylimidazole (3.7 g.) in acetic acid (30 ml.) is added dimethylsulfate (5 g.) and the mixture is heated for 16 hours on a steam bath. Dimethylsulfate (2.0 g.) is added and heating is continued for eight hours. Again dimethylsulfate (2.0 g.) is added and heating continued for 64 hours. The reaction mixture is concentrated to an oil and percent aqueous sodium hydioxide is added until neutral. The solid which separates is filtered, recrystallized from hexane and distilled in an evaporative still at 170C. and 0.3 mm. pressure to yield 1 -methyl -2-( p-chlorophenyl )-5- .trifluoromethylimidazole, m.p., 6267C.

Analysis for C H CIF N Calculated: C, 50.69; H, 3.09; N, 10.75

Found: C, 50.82; H, 3.07; N, 10.61

EXAMPLE 62 1-Methyl-2-( Z-Pyridyl )-4-and-5- Trifluoromethylimidazole An ethereal solution of diazomethane (3.0 g., 0.07 mole) is added with cooling to a solution of 2-(2- pyridyl)-4(5)-trifluoromethylimidazole (6.5 g, 0.03 mole) in ether (200 ml.). After standing overnight at room temperature the reaction solution is concentrated to a dark oil, from which the product is extracted with boiling hexane. Concentration of the hexane and distillation of the crude product at 86C. and 0.2 mm. mercury yields 2.7 g. of pure l-methyl-2-(2-pyridyl )-4-and- 5-trifluoromethylimidazole, m.p., 4249C. Vapor phase chromatography shows an 88 percent-12 percent mixture of the 4-and-5-trifluoromethyl substituted products.

EXAMPLE 63 1-Methyl-2-( 4-Pyridyl )-4-and-5- Trifluoromethylimidazole An ethereal solution of diazomethane (4.5 g., 0.107 mole) is added with cooling to a solution of 2-(4- pyridyl)-4-(5 )-trifluoromethylimidazole 10.0 g., 0.047 mole) in ether (200 ml.) and methanol (25 ml.). After standing overnight at room temperature the precipitated solid is filtered and the filtrate is concentrated to a viscous oil which is extracted with boiling hexane. On standing :1 solid separates and this material is filtered and'recrystallizedfrom water to yield 1methy1-2-(4- pyridyl)-4-triflu0romethylimidazole (930 mg.), m.p., l22124C.' The hexane filtrate is then concentrated to a solid and after recrystallization from hexane yields l-methyl-2-( 4=pyridyl )-5-trifluoromethylimidazo1e (610 mg). m.p., 50-52C.

EXAMPLE 64 1-Methy1-2 Pheny1-4-and-5-trifluoromethylimidazole An. ethereal solution of diazomethane (3.0 g., 0.07 mole) is added with cooling to a solution of 2-pheny1- 4(5)-trifluoromethylimidazole (6.4 g.. 0.03 mole) in ether (200 ml.) and methanol (15 ml.). After standing overnight at room temperature the reaction solution is concentrated to a solid and this material is extracted with boiling hexane. Concentration of the hexane extract yields crude product which is purified by column chromatography and recrystallization from hexane to yield 1-methyl-2-phenyl-4-trifluoromethylimidazole and 1-methyl-2-phenyl-5-trifluoromethylimidazole (430 mg. m.p., l071 12C. Vapor phase chromatography shows an 83 percent-17 percent mixture of isomers.

EXAMPLE 65 2-( 6-Quino1yl )-4( 5 l-Trifl uoromethylimidazole To a solution of sodium acetate trihydrate (5.8 g. 1 in water (20 ml.) is added dibromotrifluoroacetone (5.8 g.). The resulting solution is heated 0.5 hours on a steam bath cooled and added to quinoline-6- carboxaldehyde (3.4 g.) in methanol m1.) and concentrated aqueous ammonia (25 ml. The reaction mixture is allowed to stand for six hours at room tem perature and the methanol is then removed under re duced pressure. Water (25 m1.) is added whereupon a solid separates and this material is filtered and recrystallized from acetonitrile to yield 1.3 g. of 2-(6- quinolyl )-4-( 5 )-trifluoromethylimidazole, m p. 254.52S5 C.

Analysis for C H F N Calculated: C. 59.32; H, 3.06; N, 15.96

Found: C, 59.61; H. 3.00; N, 16.07

Upon substituting quinoline-4-carboxaldehyde for the quinoline-o-carboxaldehyde in the above method and otherwise following the procedure described therein, there is thus obtained 2-(4-quinolyl)-4(5)- trit'luoromethylimidazole at m.p. 206207 C.

Calculated: C, 59.32; H, 3.06; N, 15.96; F, 21.66

Found: C, 59.77; H, 3.16; N, 16.19; F, 21.36

EXAMPLE 66 2-( l-Piperidino-2-Methyl'2-Propy1)-4(5 Trifluoromethylimidazole To a solution of sodium acetate trihydrate l 1.8 g.) in water (40 m1.) is added dibromotrifluoroacetone (1 1.8 g. The resulting solution is heated 0.5 hours on a steam bath, cooled and added to 3-piperidino-2,2- dimethylpropionaldehyde (7.5 g.) in methanol (20 m1.) and concentrated aqueous ammonia (50 ml.). The reaction mixture is allowed to stand for 4.5 hours at room temperature and the methanol is then removed under reduced pressure. Water (50 ml.) is added whereupon a solid separates and this material is filtered and recrystallized from hexane to yield 1.8 g. of 2-( l-piperidino- 2-methyl-2-propy1 )-4( 5 )-triiluoromethylimidazole, m.p. 1l3.5-1l5.5C.

Analysis for C H F N Calculated: N. 15.26; C, 56.71; H, 7.32

Found: N, 15.09; C, 56.39; H. 7.09

It should be understood that although this invention has been described with reference to particular embodiments thereof. changes and modifications may be made which are within its intended scope, and it should be limited only by the language of the appended claims.

What is claimed is: l. A compound of the formula:

25 26 Hi FsC 1H1 F30 1&1 1i

and the nontoxic pharmacologically acceptable salts and the nontoxic pharmacologically acceptable salts thereof wherein R is hydrogen, C alkyl or mono hythereof wherein R is quinolyl.

droxy C, alkyl and R is quinolyl. 3. 2-(2-Quinolyl)-4(5)-trifluoromethylimidazole.

2. A compound of the formula: 4. 2-(6-Quinolyl)-4(5)-trifluoromethylimidazole. 

2. A compound of the formula:
 3. 2-(2-Quinolyl)-4(5)-trifluoromethylimidazole.
 4. 2-(6-Quinolyl)-4(5)-trifluoromethylimidazole. 